De novo Design of a Homo-Trimeric

April 2, 2020
De novo Design of a Homo-Trimeric
Models derived from neutron diffraction data. (Left) ordered water molecules and hydrogen-bond network between the polar serine residues (Ser-71) and amantadine; (Right) Residues involved in the designed hydrogen-bond networks (black dashed lines) in the ABP complex.

Scientific Achievement

Experimental structure measurements validated the first computational design of a symmetric homo-oligomer that binds to a symmetry-matched small molecule. 

Significance and Impact

The designed homo-trimeric protein binds to the FDA-approved, small-molecule drug amantadine. This is a step towards the reuse of licensed drugs for new medical treatments.

Research Details

  • Computational methods employing RosettaDesign were employed for de novo design of the protein.
  • Nuclear magnetic resonance (NMR) verified the protein’s 3-fold symmetry
  • X-ray diffraction showed a close overall match of the structure to the design model.
  • Neutron diffraction verified that hydrogen bond networks correspond to the computational design. 

“De novo design of a homo-trimeric amantadine-binding protein,”
Jooyoung Park1,2, Brinda Selvaraj3, Andrew C. McShan4, Scott E. Boyken1,2, Kathy Y. Wei1,2,5, Gustav Oberdorfer6, William DeGrado7, Nikolaos G. Sgourakis4, Matthew J. Cuneo3,8, Dean A.A. Myles3, David Baker1,2*,
eLIFE, 8, e47839 (2019).  
DOI: 10.7554/eLife.47839
https://elifesciences.org/articles/47839